One of the key pharmacological targets in the fight against AIDS is HIV-1 reverse transcriptase (RT), which controls a number of essential steps in viral replication. In the current proposal, new structural biological approaches will be applied to develop RT inhibitors. One approach will be an adaptation of the "multiple solvent crystal structures" method, in which small organic molecules are soaked into RT crystals to probe for possible inhibitor binding sites. This strategy will be augmented by a second approach, in which existing crystallographic equations will be modified to account for X-ray scattering by semi-ordered solvent molecules. This ability to phase a portion of the solvent around a protein could to lead to sharper, more interpretable electron density images of protein structure and small molecules bound to the protein. Visualization of these small bound molecules can provide the rationale for designing the backbones for new, highly specific drug prototypes. This method will be applied to improve refinement for a new class of RT inhibitors (see preliminary results). The method may advance the field of macromolecular X-ray crystallography, opening up new opportunities for structure-based drug design to treat AIDS and a variety of other disorders.